Processes for spray drying solutions of hydrophobic drugs and compositions thereof

ABSTRACT

Methods for preparing dry powders having hydrophobic and hydrophilic components comprise combining solutions or suspensions of the components and spray drying them simultaneously in a spray drier. Both the hydrophobic and hydrophilic component are dissolved in a solvent system selected to have adequate solubility for both components. The method provides dry powders having relatively uniform characteristics.

This application is a continuation-in-part of Provisional ApplicationNo. 60/034,837, filed on Dec. 31, 1996, the full disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to dry powder compositions andmethods for their preparation and use. In particular, the presentinvention relates to methods for spray drying pharmaceutical and othercompositions comprising a hydrophobic drug or other component and ahydrophilic excipient or other component.

Over the years, certain drugs have been sold in formulations suitablefor oral inhalation (pulmonary delivery) to treat various conditions inhumans. Such pulmonary drug delivery formulations are designed to beinhaled by the patient so that the active drug within the dispersionreaches the lung. It has been found that certain drugs delivered to thelung are readily absorbed through the alveolar region directly intoblood circulation. Such pulmonary delivery can be effective both forsystemic delivery and for localized delivery to treat diseases of thelungs.

Pulmonary drug delivery can itself be achieved by different approaches,including liquid nebulizers, aerosol-based metered dose inhalers(MDI's), and dry powder dispersion devices. Aerosol-based MDI's arelosing favor because they rely on the use of chlorofluorocarbons(CFC's), which are being banned because of their adverse effect on theozone layer. Dry powder dispersion devices, which don not rely on CFCaerosol technology, are promising for delivering drugs that may bereadily formulated as dry powders.

The ability to deliver pharmaceutical compositions as dry powders,however, is problematic in certain respects. The dosage of manypharmaceutical compositions is often critical, so it is desirable thatdry powder delivery systems be able to accurately, precisely, andreliably deliver the intended amount of drug. Moreover, manypharmaceutical compositions are quite expensive. Thus, the ability toefficiently formulate, process, package, and deliver the dry powderswith a minimal loss of drug is critical. With dry powder drug delivery,both the delivered dose efficiency, i.e. the percentage of drug from aunit dose receptacle which is aerosolized and delivered from a deliverydevice, and the median particle size distribution, i.e. the deviationfrom the median size, are critical to the successful delivery of powdersto a patient's lungs.

A particularly promising approach for the pulmonary delivery of drypowder drugs utilizes a hand-held device with a hand pump for providinga source of pressurized gas. The pressurized gas is abruptly releasedthrough a powder dispersion device, such as a venturi nozzle, and thedispersed powder made available for patient inhalation. Whileadvantageous in many respects, such hand-held devices are problematic ina number of other respects. The particles being delivered are usuallyless than 5 μm in size, making powder handling and dispersion moredifficult than with larger particles. The problems are exacerbated bythe relatively small volumes of pressurized gas, which are availableusing hand-actuated pumps. In particular, venturi dispersion devices areunsuitable for difficult-to-disperse powders when only small volumes ofpressurized gas are available with the handpump. Another requirement forhand-held and other powder delivery devices is efficiency. High deviceefficiency in delivering the drug to the patient with the optimal sizedistribution for pulmonary delivery is essential for a commerciallyviable product.

Spray drying is a conventional chemical processing unit operation usedto produce dry particulate solids from a variety of liquid and slurrystarting materials. The use of spray drying for the formulation of drypowder pharmaceuticals is known, but has usually been limited to spraydrying of hydrophilic drugs in aqueous solutions, usually in combinationwith hydrophilic excipients. Many drugs, however, are hydrophobic,preventing spray drying in aqueous solutions. While spray drying ofhydrophobic materials can often be accomplished using an organicsolvent, the use of such non-aqueous solvents generally limits theability to simultaneously spray dry a hydrophilic excipient.

For these reasons, it would be desirable to provide improved methods forspray drying pharmaceutical and other compositions which comprise bothhydrophobic and hydrophilic components, such as hydrophobic drugs andhydrophilic excipients. Such spray drying methods should be compatiblewith a wide variety of hydrophobic drugs as well as conventionalhydrophilic excipients, such as povidone (polyvinylpyrrolidone) andother water soluble polymers, mannitol and other water solublecarbohydrates, and particularly with those excipients which are acceptedfor use in inhalation formulations, such as lactose and sodium chloride.Such spray drying methods will preferably produce particles having auniform size distribution, with a mean particle size below 10 μm,preferably below 5 μm, and a standard deviation less than or equal to ±2μm. Such powders should further exhibit uniform composition from batchto batch so that any tendency for particles of different compositionsand/or sizes to separate in the lungs will have a reproducible impact onthe therapeutic effect. Additionally, such spray drying methods shouldprovide for dry powders which are physically and chemically stable andwhich have low levels of any residual organic solvents or othercomponents which might be used in the spray drying process. At leastsome of the above objectives will be met by the various embodiments ofthe present invention which are described in detail below.

2. Description of the Background Art

Methods for spray drying hydrophobic and other drugs and components aredescribed in U.S. Pat. Nos. 5,000,888; 5,026,550; 4,670,419, 4,540,602;and 4,486,435. Bloch and Speison (1983) Pharm. Acta Helv 58: 14-22teaches spray drying of hydrochlorothiazide and chlorthalidone(lipophilic drugs) and a hydrophilic adjuvant (pentaerythritol) inazeotropic solvents of dioxane-water and 2-ethoxyethanol-water. A numberof Japanese Patent application Abstracts relate to spray drying ofhydrophilic-hydrophobic product combinations, including JP 806766; JP7242568; JP 7101884; JP 7101883; JP 71018982; JP 7101881; and JP4036233. Other foreign patent publications relevant to spray dryinghydrophilic-hydrophobic product combinations include FR 2594693; DE2209477; and WO 88/07870.

WO 96/09814 describes spray dried pharmaceutical powders. In particular,Example 7 describes spray drying budesonide and lactose in ethanol wherethe budesonide is partially soluble and the lactose is insoluble. U.S.Pat. Nos. 5,260,306; 4,590,206; GB 2 105 189; and EP 072 046 describe amethod for spray drying nedocromil sodium to form small particlespreferably in the range from 2 to 15 μm for pulmonary delivery. U.S.Pat. No. 5,376,386, describes the preparation of particulatepolysaccharide carriers for pulmonary drug delivery, where the carrierscomprise particles sized from 5 to 1000 μm. Mumenthaler et al. (1994)Pharm. Res. 11: 12 describes recombinant human growth hormone andrecombinant tissue-type plasminogen activator. WO 95/23613 describespreparing an inhalation powder of DNase by spray drying usinglaboratory-scale equipment. WO 91/16882 describes a method for spraydrying proteins and other drugs in liposome carriers.

The following applications assigned to the assignee of the presentapplication each describe that spray drying may be used to prepare drypowders of biological macromolecules; co-pending application Ser. No.08/644,681, filed on May 8, 1996, which was a continuation-in-part ofapplication Ser. No. 08/423,515, filed on Apr. 14, 1995; applicationSer. No. 08/383,475, which was a continuation-in-part of applicationSer. No. 08/207,472, filed on Mar. 7, 1994 now abandoned; applicationSer. No. 08/472,563, filed on Apr. 14, 1995, which was acontinuation-in-part of application Ser. No. 08/417,507, filed on Apr.4, 1995, now abandoned, which was a continuation of application Ser. No.08/044,358, filed on Apr. 7, 1993, now abandoned; application Ser. No.08/232,849, filed on Apr. 25, 1994, which was a continuation ofapplication Ser. No. 07/953,397, now abandoned. WO 94/07514 claimspriority from Ser. No. 07/953,397. WO 95/24183 claims priority from Ser.Nos. 08/207,472 and 08/383,475.

SUMMARY OF THE INVENTION

According to the present invention, methods for spray drying hydrophobicdrugs and other materials are provided which overcome at least some ofthe deficiencies noted above with respect to prior spray dryingprocesses. In particular, the spray drying methods of the presentinvention permit the simultaneous spray drying of the hydrophobiccomponent with a hydrophilic component, such as a hydrophilicpharmaceutical excipient, under conditions which result in a dry powdercomprising mixtures of both the hydrophilic and hydrophobic components.Although the methods of the present invention are particularly usefulfor forming pharmaceutical compositions where the hydrophobic componentis a hydrophobic drug, usually present at from 0.01% to 95% of thepowder, and the hydrophilic component is a hydrophilic excipient,usually present at from 99.99% to 5% of the powder, the methods may beapplied more broadly to form dry powders comprising a variety ofhydrophobic and hydrophilic components at different concentrationranges, including hydrophilic drugs and hydrophobic excipients.

The spray drying methods of the present invention are compatible withmany hydrophilic pharmaceutical excipients, particularly includingmannitol, povidone, lactose and sodium chloride. Use of the latter twoexcipients is particularly preferred for powders intended for pulmonarydelivery as they are "generally recognized as safe" (GRAS) for suchapplications. The methods are also suitable for use with numeroushydrophobic drugs and nutrients, including steroids and their salts,such as budesonide, testosterone, progesterone, estrogen, flunisolide,triamcinolone, beclomethasone, betamethasone; dexamethasone,fluticasone, methylprednisolone, prednisone, hydrocortisone, and thelike; peptides, such as cyclosporin and other water insoluble peptides;retinoids, such as all-cis retinoic acid, 13-trans retinoic acid, andother vitamin A and beta carotene derivatives; vitamins D, E, and K andwater insoluble precursors and derivatives thereof; prostagladins andleukotrienes and their activators and inhibitors including prostacyclin(epoprostanol), and prostaglandins E₁ E₂ ; tetrahydrocannabinol; lungsurfactant lipids; lipid soluble antioxidants; hydrophobic antibioticsand chemotherapeutic drugs such as amphotericin B, adriamycin, and thelike.

The spray drying methods can produce a uniform particle sizedistribution. For example, the mean particle diameter can be controlledbelow 10 μm, preferably below 5 μm, with a size distribution (standarddeviation) less than ±2 μm. The particles of the powders so producedhave a minimum batch-to-batch variability in composition, and arephysically and chemically stable. The powders have minimum residualorganic solvents to the extent they may have been used in the spraydrying process.

In particular, the method of the present invention comprises at leastpartially dissolving hydrophilic component in an organic solvent orcosolvent system. The hydrophobic component is at least partiallydissolved in the same organic solvent or cosolvent system to produce asolution. The organic solvent solution or cosolvent system is then spraydried to form particles comprising a mixture of the hydrophilic andhydrophobic components. The organic solvent will be selected to providea solubility for the hydrophilic component of at least 1 mg/ml,preferably at least 5 mg/ml, and a solubility for the hydrophobiccomponent of at least 0.01 mg/ml, preferably at least 0.05 mg/ml.Usually, the hydrophilic component will have a concentration in theorganic solvent or cosolvent system solution from 1 mg/ml to 100 mg/ml,preferably from 5 mg/ml to 60 mg/ml, and the hydrophobic component willhave a concentration from 0.01 mg/ml to 10 mg/ml, preferably from 0.05mg/ml to 5 mg/ml. Suitable organic solvents or solvent systems areselected to provide such minimum solubility characteristics, but it ispreferred if the organic solvent or cosolvent system providessolubilities well in excess of the stated minimums. The use of anonaqueous solution will be advantageous for spray drying componentsthat are physically or chemically sensitive to either water while insolution or to residual moisture content in the powder. The utilizationof a nonaqueous solution will essentially eliminate the exposure of thecomponent to both water during spray drying and residual moisture in thepowder, thereby avoiding triggering the component's sensitivity towater. A presently preferred cosolvent system comprises water:ethanol ata weight ratio in the range from 80:20 to 20:80, usually from 40:60 to60:40, preferably 50:50. The utilization of a water:ethanol system ispreferred for any hydrophobic component and hydrophilic componentcombination which has adequate solubility and stability in this solventsystem, due to the low worker exposure toxicological hazard posed bythis solvent system, and because of the lack of toxicity of any residualsolvent in the powder after spray drying is complete.

Powders prepared by the above method will be collected from the spraydrier in a conventional manner for subsequent use. For use aspharmaceuticals and other purposes, it will frequently be desirable todisrupt any agglomerates which may have formed by screening or otherconventional techniques. For pharmaceutical uses, the dry powderformulations will usually be measured into a single dose, and the singledose sealed into a package. Such packages are particularly useful fordispersion in dry powder inhalers, as described in detail below.Alternatively, the powders may be packaged in multiple-dose containers.

The present invention further comprises dry powder compositions producedaccording to the methods described above, as well as unit dose andmultidose packages of such dried powder compositions containing atherapeutically effective amount of the dry powder.

The present invention further provides methods for aerosolizing a drypowder composition comprising the steps of providing an amount of drypowder composition produced by any of the methods described above andsubsequently dispersing the dry powder composition into a flowing gasstream.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram illustrating a spray drying system suitablefor performing the methods of the present invention.

DETAILED DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The present invention relates to methods for preparing compositionscomprising ultrafine dry powders having both hydrophobic and hydrophiliccomponents. The methods are particularly suitable for producingultrafine pharmaceutical dry powders where the hydrophobic component isa hydrophobic drug and the hydrophilic component is a hydrophilicexcipient. The present invention, however, may find use for preparing avariety of other compositions including pharmaceutical compositionshaving hydrophilic drugs and hydrophobic excipients and compositionsintended for non-pharmaceutical applications. The methods rely on spraydrying liquid media in which the components are solubilized orsuspended. In particular, an organic solvent or cosolvent system isselected which can solubilize both the hydrophobic and the hydrophiliccomponent.

The term "hydrophobic component" refers to materials which are insolubleor sparingly or poorly soluble in water. As used herein, suchcompositions will have a solubility below 5 mg/ml, usually below 1mg/ml. Exemplary hydrophobic drugs include certain steroids, such asbudesonide, testosterone, progesterone, estrogen, flunisolide,triamcinolone, beclomethasone, betamethasone; dexamethasone,fluticasone, methylprednisolone, prednisone, hydrocortisone, and thelike; certain peptides, such as cyclosporin cyclic peptide, retinoids,such as all-cis retinoic acid, 13-trans retinoic acid, and other vitaminA and beta carotene derivatives; vitamins D, E, and K and waterinsoluble precursors and derivatives thereof; prostagladins andleukotrienes and their activators and inhibitors including prostacyclin(epoprostanol), and prostaglandins E₁ E₂ ; tetrahydrocannabinol; lungsurfactant lipids; lipid soluble antioxidants; hydrophobic antibioticsand chemotherapeutic drugs such as amphotericin B and adriamycin and thelike.

By "hydrophilic component," it is meant that the component is highlysoluble in water and frequently capable of swelling and formation ofreversible gels. Typical aqueous solubilities of hydrophilic componentswill be greater than 5 mg/ml, usually greater than 50 mg/ml, and oftenmuch higher. In addition to their hydrophilic nature, the pharmaceuticalexcipients will generally be selected to provide stability,dispersibility, consistency and/or bulking characteristics to enhancethe uniform pulmonary delivery of the dried powder composition to apatient. For pulmonary delivery, the excipients must be capable of beingtaken into the lungs with no significant adverse toxicological effectson the lungs. Exemplary hydrophilic excipients include carbohydrates andother materials selected from the group consisting of lactose, mannitol,povidone, sodium chloride, water soluble polymers, and the like.Particularly preferred are lactose and sodium chloride which aregenerally accepted for pulmonary delivery in dry powder formulations.

The phrase "ultrafine dry powder" means a powder composition comprisinga plurality of discrete, dry particles having the characteristics setforth below. In particular, the dry particles will have an averageparticle size below 10 μm, usually below 5 μm, preferably being in therange from 0.4 to 5 μm, more preferably from 0.4 to 4 μm. The averageparticle size of the powder will be measured as mass median diameter(MMD) by conventional techniques. A particular powder sizing techniqueuses a centrifugal sedimentary particle size analyzer (Horiba Capa 700).The powders will be capable of being readily dispersed in an inhalationdevice and subsequently inhaled by a patient so that the particles areable to penetrate into the alveolar regions of the lungs.

Of particular importance to the present invention, the ultrafine dryparticle compositions produced by the method will have particle sizedistributions which enable them to target the alveolar region of thelung for pulmonary delivery of locally acting steroids, systemicallyacting proteins, and other biologically active materials that can beadministered to or through the lungs. Such compositions advantageouslymay be incorporated into unit dosage and other forms without furthersize classification. Usually, the ultrafine dry powders will have a sizedistribution where at least 90% of the powder by weight will compriseparticles having an average size in the range from 0.1 μm to 7 μm, withpreferably at least 85% being in the range from 0.4 μm to 5 μm.Additionally, it is desirable that the particle size distribution avoidhaving an excess amount of particles with very small average diameters,i.e., below 0.4 μm.

The term "dry" means that the particles of the powder have a moisturecontent such that the powder is physically and chemically stable instorage at room temperature and is readily dispersible in an inhalationdevice to form an aerosol. Usually, the moisture and residual solventcontent of the particles is below 10% by weight, usually being below 5%by weight, preferably being below 3% by weight, or lower. The moistureand residual solvent content will usually be controlled by the dryingconditions, as described in more detail below. The term "dry" furthermeans that the particles of the powder have a moisture and residualsolvent content such that the powder is readily dispersible in aninhalation device to form an aerosol. In some cases, however,non-aqueous medium may be used for dispersing the components, in whichcase the aqueous content may approach zero.

The term "therapeutically effective amount" is the amount present in thecomposition that is needed to provide the desired level of hydrophobicdrug in the subject to be treated to give the anticipated physiologicalresponse. This amount is determined for each drug on a case-by-casebasis. The term "physiologically effective amount" is that amountdelivered to a subject to give the desired palliative or curativeeffect. This amount is specific for each drug and its ultimate approvaldosage level.

The therapeutically effective amount of hydrophobic drug will vary inthe composition depending on the biological activity of the drugemployed and the amount needed in a unit dosage form. Because thesubject powders are dispersible, it is highly preferred that they bemanufactured in a unit dosage form in a manner that allows for readymanipulation by the formulator and by the consumer. This generally meansthat a unit dosage will be between about 0.5 mg and 15 mg of totalmaterial in the dry powder composition, preferably between about 1 mgand 10 mg. Generally, the amount of hydrophobic drug in the compositionwill vary from about 0.01% w/w to about 95% w/w. Most preferably thecomposition will be about 0.05% w/w to about 25% w/w drug.

Referring now to FIG. 1, processes according to the present inventionfor preparing dispersible dry powders of hydrophobic and hydrophiliccomponents comprise an atomization operation 10 which produces dropletsof a liquid medium which are dried in a drying operation 20. Drying ofthe liquid droplets results in formation of the discrete particles whichform the dry powder compositions which are then collected in aseparation operation 30. Each of these unit operations will be describedin greater detail below.

The atomization process 10 may utilize any one of several conventionalforms of atomizers. The atomization process increases the surface areaof the starting liquid. Due to atomization there is an increase in thesurface energy of the liquid, the magnitude of which is directlyproportional to the surface area increase. The source of this energyincrease depends on the type of atomizer used. Any atomizer(centrifugal, sonic, pressure, two fluid) capable of producing dropletswith a mass median diameter of less than about 20 μm could be used.Preferred for the present invention is the use of two fluid atomizerswhere the liquid medium is delivered through a nozzle concurrently witha high pressure gas stream. Particularly preferred is the use oftwo-fluid atomization nozzles as described in copending application Ser.No. 08/644,681, which is capable of producing droplets having a mediandiameter less than 20 μm.

The atomization gas will usually be nitrogen which has been filtered orotherwise cleaned to remove particulates and other contaminants.Alternatively, other gases, such as air may be used. The atomization gaswill be pressurized for delivery through the atomization nozzle,typically to a pressure above 5 psig, preferably being above 10 psig.Although flow of the atomization gas is generally limited to sonicvelocity, the higher delivery pressures result in an increasedatomization gas density. Such increased gas density has been found toreduce the droplet size formed in the atomization operation. Smallerdroplet sizes, in turn, result in smaller particle sizes. Theatomization conditions, including atomization gas flow rate, atomizationgas pressure, liquid flow rate, and the like, will be controlled toproduce liquid droplets having an average diameter below 20 μm asmeasured by phase doppler velocimetry.

The drying operation 20 will be performed next to evaporate liquid fromthe droplets produced by the atomization operation 10. Usually, thedrying will require introducing energy to the droplets, typically bymixing the droplets with a heated gas which causes evaporation of thewater or other liquid medium. Preferably, the heated gas stream willflow concurrently with the atomized liquid, but it would also bepossible to employ counter-current flow, cross-current flow, or otherflow patterns.

The drying rate may be controlled based on a number of variables,including the droplet size distribution, the inlet temperature of thegas stream, the outlet temperature of the gas stream, the inlettemperature of the liquid droplets, and the manner in which the atomizedspray and hot drying gas are mixed. Preferably, the drying gas streamwill have an inlet temperature of at least 70° C. The outlet temperaturewill usually be at least about 40° C. The drying gas will usually be airor nitrogen which has been filtered or otherwise treated to removeparticulates and other contaminants. The gas will be moved through thesystem using conventional blowers or compressors.

The separation operation 30 will be selected in order to achieve veryhigh efficiency collection of the ultrafine particles produced by thedrying operation 20. Conventional separation operations may be used,although in some cases they should be modified in order to assurecollection of sub-micron particles. In an exemplary embodiment,separation is achieved using a filter medium such as a membrane medium(bag filter), a sintered metal fiber filter, or the like. Alternatively,and often preferably, separation may be achieved using cycloneseparators, although it is usually desirable to provide for high energyseparation in order to assure the efficient collection of sub-micronparticles. The separation operation should achieve collection of atleast 80% of all particles above 1 μm in average particle size,preferably being above 85%, more preferably being above 90%, and evenmore preferably being above 95%, in collection efficiency.

In some cases, a cyclone separator can be used to separate very fineparticles, e.g. 0.1 μm, from the final collected particles. The cycloneoperating parameters can be selected to provide an approximate cutoffwhere particles above about 0.1 μm are collected while particles below0.1 μm are carried over in the overhead exhaust. The presence ofparticles below 0.1 μm in the pulmonary powder is undesirable since theywill generally not deposit in the alveolar regions of the lungs, butinstead will be exhaled.

The present invention relies on proper selection of the liquid medium ormedia for solubilizing the hydrophobic drug or other component andhydrophilic excipient or other component. An organic solvent orcosolvent is selected in which both the hydrophobic drug or othercomponent and the hydrophilic excipient or other component may bedissolved. Neither the drug nor excipient need be highly soluble in thesolvent, since both components will typically be present in the solventat relatively low concentrations, usually below 10% w/v, more usuallybelow 5% w/v. The solvent must further be selected to leave minimumresidual solvent in the spray dried product. The particular organicsolvent or cosolvent selected will depend on the nature of thehydrophobic drug and the hydrophilic excipient. Suitable organicsolvents or solvent systems may include an alcohol, ketone, hydrocarbon,polar aprotic solvent, or the like, and mixtures and aqueous solutionsthereof. The use of a nonaqueous solution will be advantageous for spraydrying components that are physically or chemically sensitive to eitherwater while in solution or to residual moisture content in the powder.The utilization of a nonaqueous solution will essentially eliminate theexposure of the component to both water during spray drying and residualmoisture in the powder, thereby avoiding triggering the component'ssensitivity to water. Exemplary combinations of drug, excipient, andsolvent are set forth in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        DRUG        EXCIPIENT                                                         (Solubility in Solvent)                                                                   (Solubility in Solvent)                                                                         SOLVENT                                         ______________________________________                                        Budesonide  Povidone          Methanol                                        (good solubility)                                                                         (highly soluble)                                                  Budesonide  Povidone          Ethanol                                         (adequate solubility)                                                                     (good solubility)                                                 Budesonide  Mannitol          Acetone (50%)/                                  (adequate solubility)                                                                     (adequate solubility)                                                                           Water (50%)                                                                   (by volume)                                     Budesonide  Lactose           DMSO (33%)/                                     (good solubility)                                                                         (adequate solubility)                                                                           Acetone (67%)                                                                 (by volume)                                     Budesonide  Lactose and/or Sodium Chloride                                                                  Ethanol (50%)/                                  (adequate solubility)                                                                     (adequate solubility)                                                                           Water (50%)                                                                   (by volume)                                     ______________________________________                                    

Each of these formulations has been spray dried and tested as describedin further detail in the Experimental section hereinafter. It should benoted that for many pharmaceutical compositions, it will be desirable toprovide the excipient at significantly higher concentrations than thedrug. Thus, when choosing a common solvent system it may be necessary tochoose solvents which provide for greater solubility for the excipientthan for the drug. A presently preferred cosolvent compriseswater:ethanol in the ratios set forth above. The utilization of anethanol/water system is preferred for any hydrophobic component andhydrophilic component combination which has adequate solubility andstability in this solvent system, due to the low worker exposuretoxicological hazard posed by this solvent system, and because of thelack of toxicity of any residual solvent in the powder after spraydrying is complete.

This spray drying method, which employs a common solubilizing solventsystem, is advantageous in that both the hydrophobic drug or othercomponent and the hydrophilic excipient or other component will be fullydissolved, enhancing product uniformity after spray drying. The fulldissolution of the component is desirable since it greatly reduces thelikelihood that the components will separate to any significant extentduring storage, delivery to the spray drier, passage through theatomization nozzle, or during the spray drying operation.

Once the dry powders have been prepared, they may be packaged inconventional ways. For pulmonary pharmaceutical applications, unitdosage forms may comprise a unit dosage receptacle containing a drypowder. The powder is placed within a suitable dosage receptacle in anamount sufficient to provide a subject with drug for a unit dosagetreatment. The dosage receptacle is one that fits within a suitableinhalation device to allow for the aerosolization of the dry powdercomposition by dispersion into a gas stream to form an aerosol and thencapturing the aerosol so produced in a chamber having a mouthpieceattached for subsequent inhalation by a subject in need of treatment.Such a dosage receptacle includes any container enclosing thecomposition known in the art such as gelatin or plastic capsules with aremovable portion that allows a stream of gas (e.g., air) to be directedinto the container to disperse the dry powder composition. Suchcontainers are exemplified by those shown in U.S. Pat. Nos. 4,227,522issued Oct. 14, 1980; 4,192,309 issued Mar. 11, 1980; and 4,105,027issued Aug. 8, 1978. Suitable containers also include those used inconjunction with Glaxo's Ventolin Rotohaler® brand powder inhaler orFison's Spinhaler® brand powder inhaler. Another suitable unit-dosecontainer which provides a superior moisture barrier is formed from analuminum foil plastic laminate. The pharmaceutical-based powder isfilled by weight or by volume into the depression in the formable foiland hermetically sealed with a covering foil-plastic laminate. Such acontainer for use with a powder inhalation device is described in U.S.Pat. No. 4,778,054 and is used with Glaxo's Diskhaler® (U.S. Pat. Nos.4,627,432; 4,811,731; and 5,035,237). Preferred dry powder inhalers arethose described in U.S. patent application Ser. Nos. 08/309,691 and08/487,184, assigned to the assignee of the present invention. Thelatter application has been published as WO 96/09085.

The following examples are offered by way of illustration, not by way oflimitation.

Experimental

The following materials were used: Budesonide (micronized to a medianparticle size of 1-2 μm; Steraloids)

Lactose monohydrate (NF grade; Foremost Ingredient Group)

Povidone (PVP K-15; ISP Technologies)

Mannitol (USP grade; Mallinckrodt)

Sodium Chloride (reagent grade from VWR and USP grade from EMIndustries)

Deionized water

Ethanol, 200 proof (USP/NF; Spectrum Chemical Mfg. Corp.)

Acetone (for histology; EM Industries)

Methanol (HPLC grade; EM Industries)

Dimethyl sulfoxide (DMSO; Photex reagent grade; J. T. Baker)

All batches were spray dried on Buchi 190 Mini Spray Dryers, withnozzles and cyclones that were designed to generate and catch very fineparticles. Since these formulations utilized organic solvents, a Buchi190 Mini Spray Dryer was used that was modified so that it was suppliedwith nitrogen as the gas source and equipped with an oxygen sensor andother safety equipment to minimize the possibility of explosion. Thesolution feed rate was 5 ml/minute, inlet temperature was adjusted toobtain the outlet temperature noted in each example, the top of thecyclone in some runs was jacketed and cooled to a temperature of about30° C, the drying nitrogen flow rate was about 18 SCFM, and theatomizing nitrogen was supplied at 0.5 to 1.5 SCFM. The powders werefurther dried in the collector for 5-15 minutes (most often for 5minutes) by maintaining approximately the outlet temperature and airvolume after the feeding of the liquid formulation was completed.

Particle size was determined with a Horiba Particle Size Analyzer, modelCAPA 700. Median particle Size refers to the volume based particle sizedistribution of the prepared bulk powders determined via centrifugalsedimentation as follows. A sample of the powder was suspended in anappropriate liquid medium (one that minimizes solubilizing theparticle), sonicated to break up the agglomerates, and then centrifuged.The median particle size was determined by measuring the sedimentationrate during centrifugation. This method provides the median size of the"primary" particle, that is, the size of the particles produced by themanufacturing process, plus potential modification during samplepreparation. Because these formulations are composed of both watersoluble and water insoluble materials, it is likely that the suspensionstep during sample preparation does to some extent solubilize part ofthe particle, and thereby modify the particle size that is determined.Therefore, the resultant particle sizes should be viewed as estimatedvalues, rather than absolute values.

Moisture content was determined by the Karl-Fischer Reagent titrimetricmethod.

Delivered dose efficiency refers to a measure of the percentage ofpowder which is drawn out of a blister package and which exits themouthpiece of an inhaler device as described in U.S. patent applicationSer. No. 08,/487,184. Delivered dose efficiency is a measure ofefficiency for the powder package/device combination. The test wasperformed by connecting a vacuum system to the device mouthpiece. Thevacuum system was set to be similar to a human inhalation with regard tovolume and flow rate (1.2 liters total at 30 liters/minute). A blisterpackage containing 0.5 to 10 mg of the formulation to be evaluated (2 to5 mg of powder was used for the following examples) was loaded into adevice which was held in a testing fixture. The device was pumped andfired, and the vacuum "inhalation" was switched on. The aerosol cloudwas thus drawn out of the device chamber by the vacuum, and the powderwas collected on a filter placed between the mouthpiece and the vacuumsource. The weight of the powder collected on the filter was determined.Delivered dose efficiency was calculated by multiplying this weight byone hundred and dividing by the fill weight in the blister. A highernumber was a better result than a lower number.

Solubilizing Both Budesonide and Excipient in an Organic Solvent System

Manufacturing Procedure

The indicated amounts of the budesonide and the excipient(s) were mixedwith the indicated amount of the liquid medium until all of the solidswere completely dissolved to form a solution. If necessary the solutionwas sonicated to fully dissolve the solids. For the examples utilizing50:50 ethanol:water as the solvent system, the indicated amount ofbudesonide was dissolved in the indicated amount of ethanol with mixing,the indicated amount of excipient(s) was dissolved in the indicatedamount of water with mixing, and then the two solutions were mixedtogether, resulting in a single solution containing all of thecomponents. The solution was spray dried, and the resulting powderpassed through a 35 mesh screen. This last step may not always berequired, but it has been found that passing the powder through a screenwill often decrease the delivered dose efficiency variability.

Table 2 shows the spray drier atomization air pressure and outlet airtemperature, the quantitative composition, a description of the particlemorphology, the moisture content where water was a component in theliquid medium, particle size, and delivered dose efficiency for eachpowder. Where the powders were passed through a 35 mesh screen, thedelivered dose efficiency results are preceded by the word "screened."It is noteworthy that the use of a 1:2 DMSO/acetone liquid mediumyielded low delivered dose efficiency results as did the formulationwhere sodium chloride was the sole excipient.

                                      TABLE 2                                     __________________________________________________________________________    Solubilizing both budesonide and excipient in an organic solvent system       Batch No., Formula No.                                                        (Spray Drier Atomization Air               Particle                           Pressure/Outlet Air           Particle                                                                              Moisture                                                                           Size                               Temperature)  Quantitative Composition                                                                      Morphology                                                                            Content                                                                            (μm)                                                                            Delivered Dose                __________________________________________________________________________                                                    Efficiency                    329-20        Budesonide 75 mg                                                                              Slightly dimpled                                                                      0.49%                                                                              2.31      47.2% (RSD = 12)         B-51          Mannitol   1425 mg                                                                            spheres           Screened:                                                                          55.4% (RSD = 7)          (15PSI/57° C.)                                                                       1:1 Acetone:DI water                                                                     50 ml                  retest:                                                                            51.2% (RSD = 10)                                                         retest:                                                                            52.2% (RSD = 13)         329-59        Budesonide 350 mg       0.51%                                                                              2.35                               B-51          Mannitol   6650 mg                Screened:                                                                          47.9% (RSD = 11)         (15PSI/57° C.)                                                                       1:1 Acetone:DI water                                                                     233 ml                                               329-79        Budesonide 350 mg       0.50%                                                                              1.93 Screened:                                                                          52.1% (RSD = 9)          B-5 1         Mannitol   6650 mg                                              (15PSI/57° C.)                                                                       1:1 Acetone/DI water                                                                     233 ml                                               329-22        Budesonide 75 mg        No water                                                                           3.59      44.8% (RSD = 20)         B-52          PVP K-15   1425 mg      in formula                              (2OPSI/66° C.)                                                                       Ethanol    50 ml                                                329-23        Budesonide 75 mg                                                                              Dimpled spheres                                                                       No water                                                                           3.39      50.2% (RSD = 22)         B-52          PVP K-15   1425 mg      in formula                              (15PSI/76° C.)                                                                       Ethanol    50 ml                                                329-46        Budesonide 75 mg                                                                              Dimpled spheres                                                                       No water                                                                           1.09      49.8% (RSD = 28)         B-52          PVP K-15   1425 mg      in formula                                                                              Screened:                                                                          60.5 (RSD = 7)           (15PSI/76° C.)                                                                       Ethanol    50 ml                                                329-62        Budesomde  350 mg       No water                                B-52          PVP K-15   6650 mg      in formula                                                                              Screened:                                                                          43.7% (RSD = 13)         (15PSI/76° C.)                                                                       Ethanol    233 ml                                               329-78-S      Budesonide 350 mg       No water                                                                           2.26                               B-52          PVP K-15   6650 mg      in formula                                                                              Screened:                                                                          44.8% (RSD = 9)          (15PSI/76° C.)                                                                       Ethanol    233 ml                                               329-25        Budesonide 75 mg                                                                              Dimpled spheres                                                                       No water                                                                           Not       46.3% (RSD = 14)         B-53          PVP K-15   1425 mg      in formula                                                                         available                                                                          Screened:                                                                          35.6% (RSD = 8)          (20PSI/66° C.)                                                                       Methanol   50 ml                                                329-30        Budesonide 75 mg        No water                                                                           4.15      13.6% (RSD = 30)         B-5           Lactose    1425 mg      in formula                              (15PSI/68° C.)                                                                       1:2 DMSO:acetone                                                                         75 ml                                                329-31        Budesonide 75 mg                                                                              Plates  No water                                                                           Not       6.5% (RSD = 45)          B-5           Lactose    1425 mg      in formula                                                                         available                          (10PSI/73° C.)                                                                       1:2 DMSO:acetone                                                                         75 ml                                                633-64-S      Budesonide 960 mg                                                                             Smooth  0.9% 1.88 Screened:                                                                          56.9% (RSD = 8)          B-125         Lactose    5040 mg                                                                            spheres                                         (105PSI/77°)                                                                         Ethanol    150 ml                                                             DI water   150 ml                                               633-25-S      Budesonide 960 mg                                                                             Highly  0.9% 1.84 Screened:                                                                          60.1% (RSD = 6)          B-120         Lactose    2520 mg                                                                            dimpled                                         (105PSI/77°)                                                                         Sodium Chloride                                                                          2520 mg                                                                            spheres                                                       Ethanol    150 ml                                                             DI water   150 ml                                               633-77-S      Budesonide 960 mg                                                                             Cubes and                                                                             0.3% 1.12 Screened:                                                                          16.2% (RSD = 19)         B-127         Sodium Chloride                                                                          5040 mg                                                                            agglomerates                                    (105PSI/77°)                                                                         Ethanol    150 ml                                                                             of cubes                                                      DI water   150 ml                                               __________________________________________________________________________

Although the foregoing invention has been described in some detail byway of illustration and example, for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

What is claimed is:
 1. A method for preparing a dry powder composition,said method comprising:at least partially dissolving a hydrophiliccomponent consisting of a hydrophilic excipient or mixture of excipientsin an organic solvent or cosolvent system; at least partially dissolvinga hydrophobic component consisting of a hydrophobic drug in the sameorganic solvent or cosolvent system to produce an organic solution,wherein the organic solvent or cosolvent system is selected so that thehydrophilic component has a concentration in the range from 1 mg/ml to100 mg/ml and the hydrophobic component has a concentration in the rangefrom 0.01 mg/ml to 10 mg/ml; and spray drying the organic solution, toform particles comprising a mixture of the hydrophilic and hydrophobiccomponents.
 2. A method as in claim 1, wherein the solvent comprises analcohol, ketone, hydrocarbon, or polar aprotic solvent, and mixtures andaqueous solutions thereof.
 3. A method as in claim 1, wherein thesolvent comprises ethanol:water at 80:20 to 20:80 by weight.
 4. A methodas in claim 1, wherein the hydrophobic component comprises a hydrophobicdrug.
 5. A method as in claim 1, wherein the hydrophobic drug is asteroid selected from the group consisting of budesonide, testosterone,progesterone, estrogen, flunisolide, triamcinolone, beclomethasone,betamethasone, dexamethasone, fluticasone, methylprednisolone,prednisone, hydrocortisone.
 6. A method as in claim 1, wherein thehydrophobic drug comprises a peptide, a retinoid, vitamin D, vitamin E,vitamin K, precursors and derivatives of these vitamins, aprostaglandin, a leukotriene, tetrahydrocannabinol, lung surfactantlipid, an antioxidant, a hydrophobic antibiotic, or a chemotherapeuticdrug.
 7. A method as in claim 1, wherein the hydrophilic componentcomprises an excipient for the hydrophobic drug.
 8. A method as in claim7, wherein the hydrophilic excipient comprises a material selected fromthe group consisting of lactose, mannitol, povidone, sodium chloride,and mixtures thereof.
 9. A method as in claim 1, further comprisingscreening the spray dried particles to disrupt agglomerates.
 10. Amethod as in claim 1, further comprising:measuring a single dosage ofthe dry powder; and sealing the single dosage in a package.
 11. A drypowder composition prepared according to claim
 1. 12. A unit dose of adry powder composition comprising a unit dose receptacle having atherapeutically effective amount of a dry powder composition accordingto claim
 1. 13. A method for aerosolizing a dry powder composition saidmethod comprising:providing an amount of a dry powder compositionaccording to claim 1; and dispersing the dry powder composition into aflowing gas stream.